Plasmodium falciparum malaria infects 5 percent of the global population and kills 2.5 million people annually. Fatalities result from an inflammatory cascade initiated by a malarial toxin. We have shown that glycosyl-phosphatidylinositol (GPI) is the major toxin responsible for pathogenesis. Immunization of mice with the detoxified P.falciparum GPI glycan NH-CH2-CH-2-PO4- (Manalpha-1-2)6Manalpha1-2Manalpha1-2Manalpha1-6Manalpha 1- 4GlcNH2 l-6myo-Inositol-l-PO4-glycerol, conjugated to a protein carrier prevented experimental cerebral malaria. Protection was also obtained following passive transfer of monoclonal antibodies to the GPI glycan. The P.falciparum GPI glycan is thus a candidate toxoid vaccine, and anti-GPI mAbs may be useful as prophylactic or therapeutic agents in humans. The experiments outlined in this proposal seek to investigate further the involvement of GPI in malarial pathology, and to elucidate the mechanism of toxin action. The GPI toxin is also profoundly immunosuppressive and we seek to investigate the basis of this phenomenon. Interestingly, GPI is the target of a novel immunological mechanism (the CD1/NK T cell pathway), and we aim to understand further this immunological phenomenon with a view to exploiting anti-GPI immune mechanisms. These areas are central to understanding the host/parasite interaction and the development of effective vaccines to several protozoal pathogens.